Extracranial implantable devices, systems and methods for the treatment of neuropsychiatric disorders

ABSTRACT

The present disclosure relates to methods, devices, and systems used for the treatment of mood, anxiety, cognitive, and behavioral disorders (collectively, neuropsychiatric disorders) via stimulation of the superficial elements of the trigeminal nerve (“TNS”). More specifically, minimally invasive systems, devices and methods of stimulation of the superficial branches of the trigeminal nerve located extracranially in the face, namely the supraorbital, supratrochlear, infraorbital, auriculotemporal, zygomaticotemporal, zygomaticoorbital, zygomaticofacial, nasal and mentalis nerves (also referred to collectively as the superficial trigeminal nerve) are disclosed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/898,685, filed Oct. 5, 2010, now issued as U.S. Pat. No. 8,958,880,which in turn claims the benefit of priority under 35 U.S.C. §119(e) tothe following applications: U.S. Application No. 61/248,827, entitled“Devices and Methods for Treatment of Psychiatric Disorders,” filed Oct.5, 2009; U.S. Application No. 61/289,829, entitled “ExtracranialImplantable Devices, Systems and Methods for Treatment ofNeuropsychiatric Disorders,” filed Dec. 23, 2009; U.S. Application No.61/305,514, entitled “Systems, Devices and Methods for Treatment ofNeurological Disorders and Conditions,” filed Feb. 17, 2010; and U.S.Application No. 61/354,641, entitled “Extracranial Implantable Devices,Systems and Methods for Treatment of Neurological Disorders,” filed Jun.14, 2010, and each of the above applications is hereby incorporated byreference as though fully set forth herein.

This application is also related to the following copendingapplications: U.S. application Ser. No. 12/898,686, entitled “Devices,Systems and Methods for Treatment of Neuropsychiatric Disorders,” nowissued as U.S. Pat. No. 8,380,315; U.S. application Ser. No. 12/898,675,entitled “Systems, Devices and Methods for the Treatment of NeurologicalDisorders and Conditions,” now issued as U.S. Pat. No. 8,688,220; U.S.application Ser. No. 12/898,696, entitled “Extracranial ImplantableDevices, Systems and Methods for Treatment of Neurological Disorders,”filed on Oct. 5, 2010, and each of the above applications is herebyincorporated by reference as though fully set forth herein.

FIELD

The present disclosure generally relates to implantable neurostimulatorsystems, devices and methods of using the same and more particularlyrelates to implantable neurostimulator systems, devices and methodsincluding at least one implantable electrode for treatingneuropsychiatric disorders by stimulating superficial, cutaneouselements of cranial nerve(s).

BACKGROUND

Psychiatric or neuropsychiatric disorders, for example depressivedisorders (DD), sometimes referred to as depression, or anxietydisorders, are traditionally treated with pharmacotherapy andpsychotherapy. However, a substantial percentage of patients with theseand other conditions do not recover despite multiple trials oftreatment. Traditionally, brain stimulation has been a primary treatmentalternative, and electroconvulsive therapy (ECT, or “electroshock”therapy) has been the dominant brain stimulation approach since thefirst part of the 20th century. ECT carries risks of memory and othercognitive side effects, considerable cost, and risks of anesthesia. Twoimplantable approaches have also been described: deep brain stimulation(DBS), in which electrodes are implanted directly within the brain, andvagus nerve stimulation (VNS) in which stimulating electrodes areimplanted on the vagus nerve in the neck. While the U.S. Food and DrugAdministration (FDA) have approved systems for deep brain stimulationfor the treatment of Parkinson's disease, DBS is presently anexperimental intervention for other neuropsychiatric conditions. Therisks of DBS include infection, hemorrhage, and injury to deep brainstructures. In reports of clinical studies with VNS, many of thepatients who undergo VNS treatments do not achieve remission, and thereis no reliable predictor of good outcomes from the implanted VNS device.

SUMMARY

One aspect of the subject matter of the present disclosure addresses theaforementioned needs by providing a method of treating psychiatricdisorders and systems and devices configured to stimulate the ophthalmic(supra-orbital), infraorbital, and mentalis branches of the trigeminalnerve, located in the face, and more specifically, by providing a methodof treating psychiatric disorders using trigeminal nerve stimulation(TNS) with minimally invasive, implantable and easy-to-use devices andsystems.

In another aspect of the present disclosure, an implantable electrodeassembly configured for trigeminal nerve stimulation is provided.

In yet another aspect of the present disclosure, a method of treatingpsychiatric disorders using the disclosed implantable electrode assemblyis provided.

In one aspect, a system for trigeminal nerve stimulation for treatmentof a neuropsychiatric disorder is disclosed. In one embodiment, thesystem includes: a pulse generator; and a subcutaneous electrodeassembly in electrical communication with the pulse generator. Theassembly includes: a first electrode comprising at least one contactconfigured for subcutaneous placement at a first region of the patient'sface, wherein the first electrode is configured to be implanted inproximity to, adjacent to or in contact with at least one branch of thetrigeminal nerve for treatment of a neuropsychiatric disorder bytrigeminal nerve stimulation, wherein the system is configured forminimal current penetration into a brain of a patient, and wherein theat least one branch of the trigeminal nerve is selected from the groupconsisting of: ophthalmic nerve, infraorbital nerve, mentalis nerve,supratrochlear nerve, infratrochlear nerve, zygomaticotemporal nerve,zygomaticofacial nerve, zygomaticoorbital nerve, nasal nerve, andauriculotemporal nerve. In some embodiments, the system further includesa second electrode comprising at least one contact configured forsubcutaneous placement at a second region of the patient's face, whereinthe second electrode is configured to be implanted in proximity to,adjacent to or in contact with at least one branch of the trigeminalnerve, wherein the at least one branch of the trigeminal nerve isselected from the group consisting of: ophthalmic nerve, infraorbitalnerve, mentalis nerve, supratrochlear nerve, infratrochlear nerve,zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbitalnerve, nasal nerve, and auriculotemporal nerve. In one embodiment, thefirst electrode and the second electrode are configured for implantationin proximity to, adjacent to or in contact with a same branch of thetrigeminal nerve. In one embodiment, the first electrode and the secondelectrode are configured for implantation in proximity to, adjacent toor in contact with a different branch of the trigeminal nerve. Thesystem may further include a wire operably connecting the pulsegenerator and the subcutaneous electrode assembly. The system mayfurther include a regulating device configured to regulate the maximumcharge balanced output current below approximately 30-50 mA. Theneuropsychiatric disorder is selected from the group consisting of: mooddisorder, cognitive disorder, behavioral disorder and anxiety disorder.In one embodiment, the pulse generator is configured to apply electricalsignals at a frequency between approximately 20 and 300 Hertz, at apulse duration between approximately 50 and 500 microseconds, at anoutput current density of not greater than approximately 25 mA/cm² andan output charge density of not greater than approximately 10microCoulomb/cm² at the cerebral cortex.

In one aspect, a subcutaneous electrode assembly for trigeminal nervestimulation for treatment of a neuropsychiatric disorder is disclosed.In one embodiment, the assembly includes a first electrode comprising atleast one contact configured for subcutaneous placement at a firstregion of the patient's face, wherein the first electrode is configuredto be implanted in proximity to, adjacent to or in contact with at leastone branch of the trigeminal nerve for treatment of a neuropsychiatricdisorder by trigeminal nerve stimulation, wherein the assembly isconfigured for minimal current penetration into a brain of a patient,and wherein the at least one branch of the trigeminal nerve is selectedfrom the group consisting of: ophthalmic nerve, infraorbital nerve,mentalis nerve, supratrochlear nerve, infratrochlear nerve,zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbitalnerve, nasal nerve, and auriculotemporal nerve. In one embodiment, theassembly may further include a second electrode comprising at least onecontact configured for subcutaneous placement at a second region of thepatient's face, wherein the second electrode is configured to beimplanted in proximity to, adjacent to or in contact with at least onebranch of the trigeminal nerve, wherein the at least one branch of thetrigeminal nerve is selected from the group consisting of: ophthalmicnerve, infraorbital nerve, mentalis nerve, supratrochlear nerve,infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial nerve,zygomaticoorbital nerve, nasal nerve, and auriculotemporal nerve. Insome embodiments, the first electrode and the second electrode areconfigured for implantation in proximity to, adjacent to or in contactwith a same branch of the trigeminal nerve. In some embodiments, thefirst electrode and the second electrode are configured for implantationin proximity to, adjacent to or in contact with a different branch ofthe trigeminal nerve. The neuropsychiatric disorder is selected from thegroup consisting of: mood disorder, cognitive disorder, behavioraldisorder and anxiety disorder.

In another aspect, a method for treating a neuropsychiatric disorder bytrigeminal nerve stimulation is disclosed. In one embodiment, the methodincludes implanting an electrode assembly in a patient, the subcutaneouselectrode assembly comprising: a first electrode comprising at least onecontact configured for subcutaneous placement at a first region of thepatient's face, wherein the first electrode is configured to beimplanted in proximity to, adjacent to or in contact with at least onebranch of the trigeminal nerve for treatment of a neuropsychiatricdisorder by trigeminal nerve stimulation, wherein the assembly isconfigured for minimal current penetration into a brain of a patient,and wherein the at least one branch of the trigeminal nerve is selectedfrom the group consisting of: ophthalmic nerve, infraorbital nerve,mentalis nerve, supratrochlear nerve, infratrochlear nerve,zygomaticotemporal nerve, zygomaticofacial nerve, zygomaticoorbitalnerve, nasal nerve, and auriculotemporal nerve; and applying electricalsignals to the electrode assembly at specified operational parameters totreat a neuropsychiatric disorder. The method may further include theassembly comprising a second electrode comprising at least one contactconfigured for subcutaneous placement at a second region of thepatient's face, wherein the second electrode is configured to beimplanted in proximity to, adjacent to or in contact with at least onebranch of the trigeminal nerve, wherein the at least one branch of thetrigeminal nerve is selected from the group consisting of: ophthalmicnerve, infraorbital nerve, mentalis nerve, supratrochlear nerve,infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial nerve,zygomaticoorbital nerve, nasal nerve, and auriculotemporal nerve. In oneembodiment, the step of applying electrical signals comprises applyingelectrical signals at a frequency between approximately 20 and 300Hertz, at a current of 0.05 to 5 milliamperes (mA) and at a pulseduration of less than or equal to 500 microseconds. In one embodiment,the step of applying electrical signals comprises applying electricalsignals at a frequency between approximately 20 and 300 Hertz, at apulse duration between approximately 50 and 500 microseconds, at anoutput current density of not greater than approximately 25 mA/cm² and acharge density of not greater than approximately 10 microCoulomb/cm² atthe cerebral cortex. The neuropsychiatric disorder is selected from thegroup consisting of: mood disorder, cognitive disorder, behavioraldisorder and anxiety disorder.

In another aspect, a kit for trigeminal nerve stimulation for treatmentof a neuropsychiatric disorder is disclosed. In one embodiment, the kitincludes the subcutaneous electrode assembly according to claim 1; andinstructions for implanting the electrode assembly in a patient fortreatment of a neuropsychiatric disorder. In one embodiment, the kit mayfurther include a pulse generator; and instructions for applyingelectrical signals to the electrode assembly for treatment of aneuropsychiatric disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure, both as to its organization and manner ofoperation, may be understood by reference to the following description,taken in connection with the accompanying drawings, in which:

FIG. 1A and FIG. 1B illustrate the location of several branches (nerves)of the trigeminal nerve and the location of the major foramina for thesuperficial branches of the trigeminal nerve;

FIG. 2A shows a subject wearing an embodiment of a system for trigeminalnerve stimulation including a subcutaneous electrode assembly providedaccording to aspects of the present disclosure;

FIG. 2B is the subcutaneous electrode assembly of FIG. 2A, wherein amulticontact electrode is shown;

FIG. 3 depicts another embodiment of a subcutaneous electrode assemblywhich may be used with the system of FIG. 2A;

FIG. 4A depicts another embodiment of a subcutaneous electrode assemblyconfigured for stimulation of a plurality of nerve branches which may beused with the system of FIG. 2A;

FIG. 4B depicts another embodiment of a subcutaneous electrode assemblyconfigured for stimulation of the auriculotemporal or zygomaticofacialnerve branches which may be used with the system of FIG. 2A;

FIG. 5A is a table showing an average of the results of four assessmenttests pre-treatment and post treatment of a treatment study forpsychiatric disorders using aspects of the present disclosure;

FIG. 5B is a bar graph of the data shown in FIG. 5A;

FIG. 5C is a graph illustrating the change over time of the data shownin FIG. 5A; and

FIG. 6 summarizes current, charge, current density and charge density ina subject exposed to transcutaneous stimulation of the supraorbitalnerve.

DETAILED DESCRIPTION

The present disclosure relates to methods, devices, and systems used forthe treatment of mood, anxiety, cognitive, and behavioral disorders(collectively, neuropsychiatric disorders) via stimulation of thesuperficial elements of the trigeminal nerve (“TNS”). More specifically,minimally invasive systems, devices and methods of stimulation of thesuperficial branches of the trigeminal nerve located extracranially inthe face, namely the supraorbital, supratrochlear, infraorbital,auriculotemporal, zygomaticotemporal, zygomaticoorbital,zygomaticofacial, nasal and mentalis nerves (also referred tocollectively as the superficial trigeminal nerve) are disclosed herein.Methods for the treatment of mood disorders and other neuropsychiatricdisorders by sTNS (subcutaneous trigeminal nerve stimulation) are alsoprovided. Systems and devices configured for therapeutic stimulation ofthe branches of the trigeminal nerves, such as the superficialtrigeminal nerve, and their methods of application are also described.

The systems, devices and methods disclosed herein provide a lessinvasive form of neurostimulation to treat a variety of neuropsychiatricdisorders including, but not limited to, mood, anxiety, cognitive, andbehavioral disorders. More specifically, an implantable or subcutaneouselectrode assembly and a system comprising the same configured fortrigeminal nerve stimulation are disclosed herein. As described in moredetail below, electrodes are not placed within the brain or nearcritical structures like the vagus nerve, carotid artery, or jugularvein. The electrodes are also not directly or physically attached oranchored to the nerve (e.g. by suturing), which requires intracranialinvasion and may cause a spinal fluid leak, infection, nerve damageand/or severe pain. Instead, subcutaneous electrodes (or an electrodeassembly) are placed at or near a region of a patient's face or craniumthat is in proximity to, adjacent to, in contact with, or distal to thetrigeminal nerve (or the relevant branch(es) thereof) by attaching tosubcutaneous or connective tissues above the periosteum or pericranium(a membrane that lines the outer surface of the skull) and below theepidermis (the outermost layer of skin). The nerve is stimulated atoperational parameters within a predefined range and that may be furtherrefined by factors such as patient history, disorder to be treated, orindividual sensitivity to the stimulation. The electrode assemblyplacement as described herein does not require intracranial invasion(i.e. implantation below the skull) thereby reducing the risks of aspinal fluid leak and infection. In some embodiments, the electrodeassembly may be placed or otherwise configured to stimulate the smallerbranches of the trigeminal nerve. That is, the assembly is placedfurther away from the brain and the main branch of the nerve.Surprisingly, placement of the assembly further away from the brain andthe main branch of the nerve is believed to be as efficacious as directattachment to the main branch of the nerve and may provide increasedsafety for the patient.

Some brain stimulation methods aim to generate currents in large volumesof the cortex and treat the brain as a bulk conductor, for example, ECT(electroconvulsive therapy) at the whole-lobe level and rTMS (repetitivetranscranial magnetic stimulation) at the large regional level (i.e.dorsolateral prefrontal cortex). Additionally, deep brain stimulation isgenerally predicated on stimulation of small but regional volumes thatlead to discharges in a very large number of cells. The systems, devicesand methods of the present disclosure send minimal, if any, current intothe brain; instead, signals are sent into the brain in order to modulatethe activity of relevant neuroanatomical structures. Without wishing tobe bound by any particular theory, the electrical pulses generatesignals in the cutaneous branches of the trigeminal nerve and theelectric fields are generally confined to the skin tissue and there isminimal, if any, leakage into the brain. These electrical pulses triggera cascade of change in neuronal signaling events that involve verylimited and precise recruitment of specific networks of neurons. Theneuroanatomic pathways allow targeted modulation of activity in areasinvolved in mood disorders, anxiety disorders, and otherneuropsychiatric conditions (locus coeruleus, anterior cingulate,insula, amygdala, and other cortical and subcortical structures). Thus,the systems, devices and methods as disclosed herein utilize the brain'sexisting infrastructure to transmit signals to the targets of interest.In the context of this disclosure minimal current penetration means (1)a charge density of approximately 0 μC/cm² at the cerebral cortex, or(2) calculated, measured, or modeled charge densities below thefollowing thresholds at the cerebral cortex: (a) at currents, chargedensities, or charge per phase not likely to cause activation ofpyramidal neurons and axons; and (b) to prevent brain injury, a chargedensity of less than 10 μC/cm² in one embodiment, and, in otherembodiments, a charge density of less than 0.001 to 0.1 μC/cm², and atcombinations of charge density and charge per phase not known to causebrain injury. In some embodiments, a lower charge density may be usedwhen the central nervous system of an individual patient is sufficientlysensitive to lower levels of stimulation that the lower level will stillpermit clinical benefit to accrue.

The following description is provided to enable any person skilled inthe art to make and use the subject matter of this disclosure. Variousmodifications, however, will remain readily apparent to those skilled inthe art, since the general principles of the disclosed subject matterhave been defined herein specifically to describe: (1) methods oftreating neuropsychiatric disorders by trigeminal nerve stimulation, (2)a system and an implantable electrode assembly configured for trigeminalnerve stimulation; and (3) methods of treating neuropsychiatricdisorders using such electrode assembly.

With reference to FIGS. 1A and 1B, the trigeminal nerve is the largestcranial nerve, and has extensive connections with the brainstem andother brain structures. The trigeminal nerve has three major sensorybranches over the face, all of which are bilateral, and highlyaccessible. The supraorbital nerve, or ophthalmic nerve, is frequentlyreferred to as the V₁ division. The infraorbital branch or maxillarynerve is commonly referred to as the V₂ division. The mentalis branch ofthe mandibular nerve is referred to as the V₃ division. The supraorbitalnerve supplies sensory information about pain, temperature, and lighttouch to the skin of the forehead, the upper eyelid, the anterior partof the nose, and the eye. The infraorbital branch supplies sensoryinformation about pain, temperature, and light touch sensation to thelower eyelid, cheek, and upper lip. The mentalis branch supplies similarsensory modalities to the skin of the lower face (e.g. jaw and tongue)and lips.

These branches exit the skull through three foramina, as shown in FIGS.1A and 1B. The supraorbital nerve or ophthalmic nerve exits at foramen1, approximately 2.1-2.6 cm from the nasal midline (in adults), and islocated immediately above the orbital ridge that is located below theeyebrow. The infraorbital branch or maxillary nerve exits at foramen 2,approximately 2.4-3.0 cm from the nasal midline (in adults) and thementalis nerve exits at foramen 3, approximately 2.0-2.3 cm from thenasal midline (in adults). Other sensory branches, including thezygomaticofacial, zygomaticoorbital, zygomaticotemporal, andauriculotemporal, arise from other foramina

Fibers from the three major branches join together to form thetrigeminal ganglion. From there, fibers ascend into the brainstem at thelevel of the pons to synapse with the main sensory nucleus of the pons,the mesencephalic nucleus of V, and the spinal nucleus and tract of V.Pain fibers descend in the spinal nucleus and tract of V, and thenascend to the ventral posterior medial nucleus (VPM) of the thalamus,and then project to the cerebral cortex. Light touch sensory fibers arelarge myelinated fibers, which ascend to the ventral posterior lateral(VPL) nucleus of the thalamus, and also project to the cerebral cortex.Afferent sensory fibers project from the trigeminal nuclei to thethalamus and the cerebral cortex.

The trigeminal nucleus has reciprocal projections to the nucleus tractussolitarius (NTS), the locus coeruleus, and the vagus nerve. The NTSreceives afferents from the vagus nerve and trigeminal nerve. NTSintegrates input from multiple sources, and projects to structures inthe brainstem and forebrain, including the locus coeruleus.

The locus coeruleus is a paired nuclear structure in the dorsal pons,and is located just beneath the floor of the fourth ventricle. The locuscoeruleus has extensive axonal projections to a broad number ofbrainstem, sub-cortical and cortical structures, and is an importantpart of the reticular activating system. The locus coeruleus is a corepart of the brainstem noradrenergic pathway, and produces theneurotransmitter norepinephrine. Norepinephrine plays a key role inattention, alertness, blood pressure and heart rate regulation, anxiety,and mood.

While not wishing to be bound by any particular theory, in certainembodiments, the connections between the trigeminal nerve and the locuscoeruleus, thalamus, amygdala, anterior cingulate, and other centralnervous system structures as described above may be relevant to apotential role of the trigeminal nerve in numerous neuropsychiatricdisorders, including mood (such as depression), anxiety (such aspost-traumatic stress disorder), and others, as may be apparent to oneskilled in the art. Thus, subcutaneous stimulation of the trigeminalnerve could be effective in the treatment of neuropsychiatric disorders.

For a discussion of certain embodiments of methods, systems and devicesusing subcutaneous electrodes according to aspects of the presentdisclosure, reference is now made to FIGS. 2A-4, which show variousembodiments of the systems and devices that may be used for thesubcutaneous stimulation of the superficial branches of the trigeminalnerve and methods of using the same.

According to one aspect of the present disclosure, a method of treatingneuropsychiatric disorders using trigeminal nerve stimulation (“TNS”) isprovided. In some embodiments, the method of treating these disorders bystimulating superficial branches of the trigeminal nerve comprisesimplanting electrodes adjacent to, in proximity to, or distal to atleast one of the three paired foramina or superficial branches of thetrigeminal nerves in the face (FIGS. 1A and 1B), and stimulating theelectrodes using a neurostimulator for a fixed time at specifiedoperational parameters. The electrode assembly placement does notrequire intracranial invasion (i.e. implantation below the skull)because the electrode assembly is attached or otherwise anchored tosubcutaneous or connective tissues located above the periosteum orpericranium and below the epidermis in order to place the electrodeassembly in proximity to, adjacent to, in contact with or distal to thetarget nerve branch. In some embodiments, the electrode assembly may beconfigured to stimulate the smaller branches of the trigeminal nerve.Surprisingly, placement of the assembly further away from the brain andthe main branch of the nerve is believed to be as efficacious as directattachment or other contact with the main branch of the nerve and mayprovide increased safety for the patient.

In one embodiment, the implanted electrodes are positioned adjacent tothe foramina of the supraorbital or ophthalmic nerves (FIG. 1A, Foramen1) since unilateral stimulation or bilateral stimulation of thetrigeminal nerve is achievable by placing single or separate electrodeson the right and/or left sides. In one embodiment, the electrodeassembly is configured for unilateral stimulation. In one embodiment,the electrode assembly is configured for bilateral stimulation. In someembodiments, bilateral stimulation may offer similar or better efficacythan unilateral stimulation because the function of different brainstructures may not be the same on right and left (e.g. verbal expressionis most commonly localized to speech centers in the left hemisphere, andinjury there produces catastrophic loss of the ability to speak, whiledamage to the corresponding region on the right does not produce thisprofound loss of function, but may alter subtle functions). There mayalso be synergistic effects that arise with bilateral stimulation. FIG.2A shows an example of a patient 10 who has been implanted with twoseparate electrodes 12 in the soft tissues of the forehead, one overeach eyebrow, corresponding to the foramina of the ophthalmic nerves. Inalternative embodiments, the implanted/implantable electrode(s) can bepositioned adjacent to or in proximity to the infraorbital foramen(infraorbital nerves) (FIG. 1A, Foramen 2) or the mentalis foramen(mentalis nerves) (FIG. 1B, Foramen 3). In other embodiments, electrodesmay be placed adjacent to, in proximity to, or in contact with thesupratrochlear nerve, infratrochlear nerve, zygomaticotemporal,zygomaticofacial, zygomaticoorbital, nasal, and/or auriculotemporalnerves and/or their respective foramina In yet other embodiments, thestimulation can be unilaterally applied near one superficial foramen ofthe trigeminal nerves. Unilateral stimulation or bilateral stimulationof the trigeminal nerve is achievable by placing single or separateelectrodes on the right and/or left sides of the face to unilaterallyapply stimulation near one superficial foramen of the trigeminal nerves.In other embodiments, the method of treating neuropsychiatric disorderscomprises implanting electrodes over a plurality of superficial foraminain the face and simultaneously or asynchronously stimulating differenttrigeminal nerves. In other embodiments, the stimulation may take placein the cutaneous territories of branches of the trigeminal nerves,without attachment to the nerves.

In one embodiment, as can be understood from FIGS. 2A-4, a system 200for treatment of neuropsychiatric disorders via TNS includes anelectrode assembly 20, electrical cable or wire 40 and a neurostimulatoror pulse generator 30.

The pulse generator may be any type of appropriate stimulating, signalgenerating device. In some embodiments, the pulse generator 30 mayinclude electronic circuitry for receiving data and/or power fromoutside the body by inductive, radio-frequency (RF), or otherelectromagnetic coupling. In some embodiments, electronic circuitryincludes an inductive coil for receiving and transmitting RF data and/orpower, an integrated circuit (IC) chip for decoding and storingstimulation parameters and generating stimulation pulses, and additionaldiscrete electronic components required to complete the electroniccircuit functions, e.g. capacitor(s), resistor(s), transistor(s),coil(s), and the like.

In other embodiments, neurostimulator 30 may include a programmablememory for storing a set(s) of data, stimulation, and controlparameters. Among other things, memory may allow stimulation and controlparameters to be adjusted to settings that are safe and efficacious withminimal discomfort for each individual. Specific parameters may providetherapeutic advantages for various psychiatric disorders. For instance,some patients may respond favorably to intermittent stimulation, whileothers may require continuous stimulation to treat their symptoms.

In some embodiments, the neurostimulator 30 may include a power sourceand/or power storage device. Possible options for providing power to thesystem include but are not limited to: an external power source coupledto neurostimulator 30, e.g., via an RF link, a self-contained powersource utilizing any suitable means of generation or storage of energy(e.g., a primary battery, a replenishable or rechargeable battery suchas a lithium ion battery, an electrolytic capacitor, a super-capacitor,a kinetic generator, or the like), and if the self-contained powersource is replenishable or rechargeable, means of replenishing orrecharging the power source (e.g., an RF link, an optical link, athermal link, an inductive link, or other energy-coupling link).

In some embodiments, neurostimulator 30 operates independently. In otherembodiments, neurostimulator 30 operates in coordination with otherimplanted device(s) or other device(s) external to the patient's body.For example, a neurostimulator may communicate with other implantedneurostimulators, other implanted devices, and/or devices external to apatient's body via, e.g., an RF link, an ultrasonic link, a thermallink, an optical link, or the like. Specifically, a neurostimulator maycommunicate with an external remote control (e.g., patient and/orphysician programmer) that is capable of sending commands and/or data toa neurostimulator and that may also be capable of receiving commandsand/or data from a neurostimulator.

In one embodiment, the electrical cable or wire 40 is configured toprovide a physical and electrical link between the pulse generator 30and the electrode assembly 20. In other embodiments, the pulse generator30 and the electrode assembly 20 communicate wirelessly (i.e. the wire40 is not used). The system 200 and/or the electrode assembly 20 may bepart of a kit. In some embodiments, the kit may also includeinstructions for treatment of a neuropsychiatric disorder according to amethod disclosed herein.

In some embodiments, the system may include a regulation device. Theregulation device is configured to be attached to the pulse generator 15and is configured to govern the maximum charge balanced output currentbelow approximately 30-50 mA to minimize current penetration to thebrain and increase patient tolerance. The regulation device may beinternally programmed to range from 0.25-5.0, 0-10, 0-15 mA depending onthe surface area, placement, and orientation of the electrode, andwhether the electrode is stimulating near or adjacent to the skull, oraway from the skull, (mentalis), where current ranges may be higher orlower. Current TENS units stimulate with maximum output currents of upto 100 mA's, which result in currents which may penetrate the skull andwhich may not be well tolerated.

In one embodiment, as shown in FIGS. 2A-2B, the electrode assembly 20 isalso referred to as a bilateral supraorbital electrode. The electrodeassembly 20 is connectable to an implanted/implantable neurostimulatorby electrical cables 40. Alternatively, the electrodes may beconnectable to an external neurostimulator wirelessly, with transfer ofenergy across the skin by inductive coupling between a coil implanted inthe patient and a coil in the external neurostimulator.

In one embodiment, as illustrated in FIG. 2B, an electrode assembly 20may include electrodes 20 a, 20 b configured for the bilateralsimultaneous and asynchronous stimulation of the ophthalmic nerves andother nerves as described herein. The electrodes 20 a, 20 b of theelectrode assembly 20 comprise a first pair of contacts 112 a, 112 bconfigured for implantation in a first region of the patient's face,such as the patient's right forehead, and a second pair of contacts 112c, 112 d configured for implantation in a second region of the patient'sface, such as in the patient's left forehead. In other embodiments, thefirst and second regions of the patient's face may be on the same sideof the face, e.g. the right or left side, but may be at differentlocations, e.g. the right forehead or the right upper face area, theright cheek area or middle face area or the right lower face area ormouth/jaw area. The electrode assembly 20 may also include an insulatedregion 116 or a plurality of insulated regions 116 configured toseparate the individual electrode contacts. The first pair of contactscomprises a first upper contact 112 a and a first lower contact 112 b,while the second pair of contacts comprises a second upper contact 112 cand a second lower contact 112 d. The electrode assembly 20 comprisesfour electrodes that deliver the stimulation pulses to the nervesbilaterally. While the electrode assembly 20 is shown in FIG. 2B withonly pairs of electrical contacts (112 a/b, 112 c/d), in otherembodiments, there may be a greater or lesser number of contacts on eachof the assemblies 20 a and 20 b.

FIG. 3 shows another embodiment of an electrode assembly 20 that may beused in the system 200. FIG. 3 shows an example of a patient 10 who hasbeen implanted with the electrode assembly 20, provided in accordancewith the present disclosure. In one embodiment, as shown in FIG. 3, theelectrode assembly may comprise two implanted electrodes 20 a, 20 bwhich are placed adjacent to the supraorbital foramina, located over theorbital ridge approximately 2.1 to 2.6 cm lateral to the nasal midline.As shown in FIG. 3, the superior ends 13 a, 13 b of the electrodes 20 a,20 b indicate the place at which the electrodes 20 connect to leads (seeFIG. 2A) for conveying the electrical stimuli from the neurostimulator(see FIG. 2A). The neurostimulator itself may be placed in a variety oflocations under the skin, such as pectorally, and the leads placed underthe skin of the patient to connect them.

In some embodiments, such as the embodiments shown in FIGS. 2A-3, theneurostimulation may be provided using an electrical neurostimulator atthe following exemplary settings: frequency between approximately 20-150Hz, current between approximately 0.05-20 mA, pulse duration of betweenapproximately 50-250 microseconds, a duty cycle of 10% to 50%, for atleast one hour per day. For patient comfort and low power consumption,stimulation parameters at the lower end of these ranges may bepreferred. In other embodiments, different values of the operationalparameters may be used. In alternative embodiments, a single implantedelectrode with one or more contacts can be used.

FIG. 4A depicts still another embodiment of an electrode assembly 20that may be used in the system 200. In some embodiments, as shown inFIG. 4A, the electrode assembly 20 may comprise a multicontact electrode20 c with a plurality of contacts 112 and a plurality of insulatedregions 116. The electrode assembly of FIG. 4A is configured tounilaterally stimulate both the supraorbital nerve and the infraorbitalnerve. In other embodiments, the electrode assembly may comprise aplurality of multicontact electrodes which may include a plurality ofcontacts and a plurality of insulated regions. In various embodiments,the geometry or layout of the electrode assembly may be a linearelectrode with a single contact or a series or plurality of conductivecontacts and insulating spaces, or a flatter, “ribbon” or “strip”electrode, also with the possibility of one or more conductive area(s)and insulated area(s) on the surface(s). Those of skill in the art willrecognize that other related geometries are also contemplated to bewithin the scope of the present disclosure.

As can be understood from FIG. 4A, in one embodiment, the electrodeassembly may be implanted unilaterally. The electrode assembly may alsobe configured to stimulate more than one nerve. For example, as shown inFIG. 4A, the electrode assembly is configured to be placed at, near orover a plurality of superficial foramina in the face and simultaneouslyor asynchronously stimulate different trigeminal nerves (e.g. thesupraorbital nerve and the infraorbital nerve).

FIG. 4B depicts still another embodiment of an electrode assembly 20that may be used in the system 200. In some embodiments, as shown inFIG. 4B, the electrode assembly 20 may comprise a multicontact electrode20 d with a plurality of contacts 112 and a plurality of insulatedregions 116. The electrode assembly of FIG. 4B is configured tounilaterally stimulate at least one of the auriculotemporal nerve or thezygomaticofacial nerve. In other embodiments, the electrode assembly 20d may be configured to stimulate both the auriculotemporal nerve and thezygomaticofacial nerve. As can be understood from FIG. 4B, in oneembodiment, the electrode assembly may be implanted unilaterally. Theelectrode assembly is configured to be placed at, near or over asuperficial foramina in the face and simultaneously or asynchronouslystimulate one or more different trigeminal nerves (e.g. theauriculotemporal nerve and/or the zygomaticofacial nerve).

Those skilled in the art will appreciate that various adaptations andmodifications of the above-described embodiments of the electrodeassembly 20 are within the scope and spirit of the present disclosure.For example, one embodiment of the present device comprises a unilateralelectrode assembly configured for the unilateral stimulation ofophthalmic nerves (see FIGS. 4A-4B). In other embodiments, theimplantable electrode assembly may be configured for the stimulation ofthe infraorbital nerves or the mentalis nerves. In other embodiments,the electrode assembly may be configured for the stimulation of theauriculotemporal nerve. In one embodiment, the electrode assembly may beconfigured for the stimulation of the zygomaticofacial nerve. In otherembodiments, an electrode assembly may be configured for thesimultaneous or asynchronous stimulation of a plurality of elements ofthe trigeminal nerves, either unilaterally or bilaterally. In otherembodiments, both external, transcutaneous electrodes and implantedsubcutaneous electrodes are used to simultaneously or asynchronouslystimulate one or more branches of the trigeminal nerves. The external,transcutaneous electrode assemblies are described in copending U.S.patent application Ser. No. 12/898,686.

For ease of the reader, the remaining discussion is made with respect toFIG. 2B. However, it is understood that the disclosure also applies toembodiments which include a single multicontact electrode with aplurality of contacts, a single contact electrode, and embodiments whichinclude a plurality of multicontact electrodes with a plurality ofcontacts and embodiments configured for unilateral or bilateralstimulation and other embodiments within the spirit and scope of thepresent disclosure.

As can be understood from FIG. 2B, the electrode assembly 20 isconfigured to stimulate both the right and left ophthalmic nerves eithersimultaneously or asynchronously. The placement of the first implantedelectrode with contact pair 112 a, 112 b and the second electrode withcontact pair 112 c, 112 d on opposite sides of the nasal midline assuresthat stimulation current moves orthodromic ally or in the direction ofthe afferent ophthalmic or supraorbital nerve. Furthermore, thisconfiguration of the electrode assembly 20 allows the electrode contactpoints 112 a/ 112 b and 112 c/ 112 d to be stimulated independentlyand/or unilaterally, as the response to stimulus may be localized andthus varied from one side of the midline to the other side. Depending onthe location of the pulse generator, in some embodiments, the electrodesand/or their connectors (e.g. the wires 40) are longer than 150 mm wherethe supraorbital, infraorbital and/or the mentalis branch is the desiredtarget. For other branches, a shorter electrode/connector length may bedesired depending on the placement of the pulse generator.

For stimulations where electrical pulses of a single polarity aregenerated, the upper electrode contact points 112 a, 112 c and lowercontact points 112 b, 112 d have fixed polarities. For stimulationswhere electrical pulses of alternating polarities are generated, theupper contact points 112 a, 112 c and lower contact points 112 b, 112 dhave alternating polarities.

Each of the contacts 112 a, 112 b, 112 c, 112 d is configured to deliveran electrical pulse with minimal scalp tissue injury due to excesscharge accumulation, and with minimal potential for current penetrationbeyond the inner surface of the skull bone. The distance between thefirst implanted electrode contact pair 112 a, 112 b and the secondelectrode contact pair 112 c, 112 d is configured to stimulate theophthalmic nerves while minimizing any current delivery to the surfaceof the brain. The electrode size and the inter-electrode distance ofelectrode placement may vary for children and adults, males and females,depending upon the dimensions of an individual person's anatomy.

Electrode assembly 20, and in particular the contact points 112 a, 112b, 112 c, 112 d, may be made of a noble or refractory metal or compound,such as titanium, titanium nitride, platinum, iridium, tantalum,niobium, rhenium, palladium, gold, nichrome, stainless steel, or alloysof any of these, in order to avoid corrosion or electrolysis which coulddamage the surrounding tissues and the device. Other compounds forimplantable electrodes will be apparent to one skilled in the art.

In various embodiments, the distance between contacts 112 a and 112 band the distance between contacts 112 c and 112 d can be in a rangegreater than, equal to, and/or less than one or more of 0.1 cm, 0.5 cm,1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, or 10 cm. Those ofskill in the art will recognize that one or more of the above distancescan be used as a border of a range of distances.

Those skilled in the art will appreciate that various adaptations andmodifications of the above-described embodiments of the electrodeassembly 20 are within the scope and spirit of the present disclosure.For example, one embodiment of the present device comprises a unilateralelectrode assembly configured for the unilateral stimulation ofophthalmic nerves. In other embodiments, the implantable electrodeassembly may be configured for the stimulation of the infraorbitalnerves or the mentalis nerves. In other embodiments, an electrodeassembly may be configured for the simultaneous stimulation of aplurality of elements of the trigeminal nerves.

In some embodiments, both external, transcutaneous electrodes andimplanted electrodes are used to simultaneously or asynchronouslystimulate one or more branches of the trigeminal nerves.

In some embodiments, sensing electrodes are included in the electrodearray to monitor physiological parameters, such aselectroencephalographic data, and permit a feedback system that canadaptively adjust the stimulation parameters to optimize therapeuticbenefit and safety. In some embodiments, the sensing electrode is one ofthe stimulating electrodes and is used for sensing during the ‘off partof the duty cycle. In some embodiments, the sensing electrode is anadditional electrode and is dedicated to sensing only.

As can be best understood from FIGS. 2A-2B, the electrode assembly 20 isimplanted in the soft tissues of the forehead of the patient 20. Theelectrode 20 is then connected to an implanted neurostimulator 30 viathe implanted electrical cables 40, which are placed under the patient'sskin. In the illustrated embodiment, the stimulation via theneurostimulator 30 is via electrical cables 40. In alternativeembodiments, the electrical stimulation can be performed wirelessly,with an external, non-implanted neurostimulator, which uses inductivecoupling to deliver energy to the implanted electrode assembly 20. Thestimulation is carried out at the above-described values of theoperational parameters. The values of the operational parameters areadvantageously selected such that a patient will experience astimulation sensation, such as mild tingling over the forehead andscalp, without causing the patient significant discomfort or pain andwith minimal current penetration to the brain. These values may varyaccording to the treatment of interest.

The stimulation is carried out at the operational parameters asdescribed herein. In some embodiments, the values of the operationalparameters may be selected such that a patient will experience astimulation sensation, such as mild tingling over the forehead, scalp,or teeth, without causing the patient significant discomfort or pain.These values may vary according to the treatment of interest.

According to one aspect of the present disclosure, there is provided amethod of treatment of neuropsychiatric disorders using the electrodeassembly 20, as described above. In one embodiment, the method oftreating psychiatric disorders comprises implanting the electrodeassembly 20 to the forehead of a patient, connecting the electrodeassembly 20 to a neurostimulator 30, and stimulating the electrodeassembly 20 at defined values of the operational parameters. In oneembodiment, the bilateral supraorbital electrode 20 as disclosed hereinis stimulated at a stimulus frequency between about 20 and about 300 Hz,at a pulse duration between 50 microseconds (μsec) to 250 μsec, at anoutput current of less than 10 mA for at least one-half to one hour perday. In some cases, stimulation can be provided for less than one-halfhour per day or may be provided for up to 24 hours per day.

Accepted standards of safe stimulation may be incorporated for chronicstimulation. Parameters may be selected or calculated to deliver nostimulation or negligible stimulation to the surface of the brain. Thecurrently accepted safe parameters for chronic stimulation are less thana charge per phase of <20 μC/cm²/phase at the surface of the brain (ExpNeurol 1983; 79:397-41). In general, for any region of the surface ofthe brain, the cumulative charge per phase resulting from all theelectrode contacts should not exceed this threshold. It is recognizedthat these guidelines are subject to change, and that parameters shouldbe selected which deliver no current or negligible current to thesurface of the brain, while still being sufficient to stimulate thenerves disclosed herein.

According to one aspect of the present disclosure, the method oftreating neuropsychiatric disorders by TNS comprises selecting optimalvalues for the operational parameters for the stimulation of eachindividual patient. In one embodiment, the values of the operationalparameters are selected such that a patient will experience astimulation sensation, such as a mild tingling over the forehead, scalp,or face, without being in discomfort or in pain. In some embodiments,lower currents (e.g. 0.05-5 mA) and careful electrode placement may beselected to avoid recruitment of nerves supplying pain sensation to theteeth. In some embodiments, lower currents (e.g. 0.05-5 mA) may also beselected to avoid penetration of the current into the skull and brain,especially in supraorbital locations.

In one embodiment, the method of selecting operational parameterscomprises evaluating variables such as the pulse duration, the electrodecurrent, the duty cycle and the stimulation frequency; the parametersare selected to ensure that the total charge, the charge density, andcharge per phase are well within accepted safety limits for the scalp orfacial tissue, nerve and brain. Additionally, in some embodiments,selection of the electrical stimulation parameters, electrode design,and inter-electrode distance is made such that the electricalstimulation zone includes the superficial elements of the trigeminalnerves (approximately 3-4 mm deep), while preventing or minimizingcurrent penetration beneath the bone tissue of the skull.

In various embodiments, the stimulation parameters delivered by theimplanted pulse generator may be determined (programmed) at the time thedevice is surgically implanted. In other embodiments, these parametersmay be modified, controlled, or otherwise programmed by an externaldevice. This external programming element communicates with theimplanted components wirelessly. This may take place, for example, byradiofrequency signals, by inductive coupling, or other means apparentto one skilled in the art.

In various embodiments, the stimulation is delivered at a specific pulsewidth or range of pulse widths. The stimulation can be set to deliverpulse widths in the range greater than and/or less than one or more of50 μs, 60 μs, 70 μs, 80 μs, 90 μs, 100 μs, 125 μs, 150 μs, 175 μs, 200μs, 225 μs, 250 μs, up to 500 μs. Those of skill in the art willrecognized that one or more of the above times can be used as a borderof a range of pulse widths.

In some embodiments, the stimulation amplitude is delivered as a voltageor current controlled stimulation. In other embodiments it can bedelivered as a capacitive discharge. In various embodiments, the currentamplitude can be in any range within a lower limit of about 300 μA andan upper limit of about 30 mA-35 mA, depending on the surface area ofthe electrodes, inter-electrode distance, the branch(es) stimulated, andthe modeling data as described above. In some embodiments, the currentused will range from 0.1 mA to 10 mA. In other embodiments, the currentused will range from 0.1-3 mA. In various embodiments, the amplitude canbe in a range greater than and/or less than one or more of 50 μA, 75 μA,100 μA, 125 μA, 150 μA, 175 μA, 200 μA, 225 μA, 250 μA, 275 μA, 300 μA,325 μA, 350 μA, 375 μA, 400 μA, 425 μA, 450 μA, 475 μA, 500 μA, 525 μA,550 μA, 575 μA, 600 μA, 625 μA, 650 μA, 675 μA, 700 μA, 725 μA, 850 μA,875 μA, 900 μA, 925 μA, 950 μA, 975 μA, 1 mA, 2 mA, 3 mA, 4 mA, 5 mA, 6mA, 7 mA, 8 mA, 9 mA, 10 mA, 20 mA. Those of skill in the art willrecognize that one or more of the above amplitudes can be used as aborder of a range of amplitudes. The current may be delivered constantlyor intermittently.

In some embodiments, treatment at a given current amplitude is deliveredso as to minimize or eliminate any spread of current to the cerebralcortex, while ensuring that accepted limits of charge density and chargeper phase at the brain surface (e.g., generally <20 μC/cm²/phase, ExpNeurol 1983; 79:397-411) are adhered to, for the safety of the patient.Without wishing to be bound by any particular theory, it is believedthat with the use of multicontact electrodes as described herein, evenlower charge densities may be employed because more fibers within thenerves may be engaged in the neurostimulation process.

In various embodiments, the stimulation can be delivered at one or morefrequencies, or within a range of frequencies. The stimulation can beset to be delivered at frequencies less than, and/or greater than one ormore of 50 Hz, 45 Hz, 40 Hz, 35 Hz, 30 Hz, 25 Hz, 20 Hz, 15 Hz, or 10Hz. In various embodiments, the stimulation can be set to be deliveredat frequencies greater than, and/or less than, one or more of 20 Hz, 30Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 125 Hz, 150 Hz, upto 300 Hz. Those of skill in the art will recognize that one or more ofthe above frequencies can be used as a border of a range of frequencies.

In various embodiments, the stimulation is delivered at a specific dutycycle or range of duty cycles. The stimulation can be set to bedelivered at a duty cycle in the range greater than and/or less than oneor more of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, toensure preservation of the nerve, a duty cycle of 10% to 50% may bepreferable. In some embodiments, duty cycles up to 100% may be useful inparticular circumstances. Those of skill in the art will recognized thatone or more of the above percentages can be used as a border of a rangeof duty cycles.

According to one aspect of the present disclosure, the method oftreating psychiatric disorders by TNS comprises selecting optimal valuesfor the operational parameters for the stimulation of each individualpatient. In one embodiment, the values of the operational parameters areselected such that a patient will experience a stimulation sensation,such as a mild tingling over the forehead, scalp, or face without beingin discomfort or in pain. In some embodiments, lower currents andcareful electrode placement may be selected to avoid recruitment ofnerves supplying pain sensation to the teeth. In some embodiments, lowercurrents may also be selected to avoid penetration of the current intothe skull and brain, especially in supraorbital locations. In someembodiments, the neurostimulation parameters are important factors inthe treatment method. In one embodiment, the method of selectingoperational parameters comprises evaluating variables such as the pulseduration, the electrode current, the duty cycle and the stimulationfrequency; the parameters are selected to ensure that the total charge,the charge density, and charge per phase are well within accepted safetylimits for the scalp or facial tissue, nerve and brain. Additionally, insome embodiments, selection of the electrical stimulation parameters,electrode design, and inter-electrode distance is made such that theelectrical stimulation zone includes the superficial elements of thetrigeminal nerves (approximately 3-4 mm deep), while preventing orminimizing current penetration beneath the skull bone.

In various embodiments, the stimulation parameters delivered by theimplanted neurostimulator may be determined (programmed) at the time thedevice is surgically implanted. In other embodiments, these parametersmay be modified, controlled, or otherwise programmed by an externaldevice. This external programming element communicates with theimplanted components wirelessly. This may take place, for example, byradiofrequency signals, by inductive coupling, or other means apparentto one skilled in the art.

In some embodiments, an external device may be used to identify thelocation of the branch or branches of the trigeminal nerve that will betargeted in an individual patient for stimulation by the implantedelectrode assembly disclosed herein. The external device may be used formapping and targeting the desired branch or branches of the trigeminalnerve and for identifying the individual stimulation parameters that areoptimal for efficacy and safety. In one embodiment, the device mayinclude a plurality of external (transcutaneous) TNS electrodes. Thepractitioner approximates the location of the target branch and affixesthe electrodes to the patient's skin above the target location.Stimulation may be applied and the actual location or preferred(optimal) stimulation location of the target branch or branches may bedetermined. Stimulation parameters may also be established. Once thelocation and/or stimulation parameters have been established via theexternal device, that data may be used to help guide the placement ofthe implanted electrodes for an individual patient and to establish thecustomized stimulation parameters for that patient.

In addition, the use of external electrodes for stimulation of thetrigeminal nerve may identify individuals who are likely to derivetherapeutic benefit from this minimally invasive system in addition tothe optimal specific locations and parameters of stimulation based onperson-to-person variability. Various neurodiagnostic, imaging, orcutaneous nerve mapping methods may be able to delineate differences inindividual anatomy to optimize stimulation for efficacy and/or safety.Furthermore, the use of this minimally invasive system may allowscreening and identification of those individuals who are likely toderive benefit from other implantable systems, such as deep brainstimulation. This can be conceptualized as linking the three approachesas stage I (external TNS of the trigeminal nerve), stage II (implantedTNS of the superficial trigeminal nerve), and stage III (deep brainstimulation), such that stage I can screen for stage II, and stage IIfor stage III. By monitoring a patient for evidence of usefultherapeutic effect, such as by reduction in the severity of symptoms,the results of treatment at one stage may be used to judge the likelyeffect of treatment with a more invasive treatment from a higher stage.

A method of evaluating the use of trigeminal nerve stimulation fortreatment of a neurological disorder in a patient is disclosed herein.The method may include applying a transcutaneous system for stimulationof the trigeminal nerve to the patient and monitoring the patient for atleast one of evidence of a useful therapeutic response or evidence oftolerability of TNS treatment, providing a subcutaneous electrodeassembly or system as disclosed herein, and implanting the subcutaneouselectrode assembly or system as disclosed herein in the patient fortreatment of a neurological disorder.

A method of evaluating the use of deep brain stimulation for treatmentof a neurological disorder in a patient is disclosed herein. The methodmay include applying a transcutaneous system for stimulation of thetrigeminal nerve to the patient and monitoring the patient for at leastone of evidence of a useful therapeutic response or evidence oftolerability of TNS treatment thereby generating external measurementcriteria, providing a subcutaneous electrode assembly or system asdisclosed herein, implanting the subcutaneous electrode assembly orsystem as disclosed herein in the patient for treatment of aneurological disorder, monitoring the patient for at least one of auseful therapeutic response or tolerability of the implanted device,thereby generating extracranial measurement criteria, and analyzing theexternal measurement criteria and extracranial measurement criteria todetermine whether the patient will benefit from deep brain stimulation.

The following examples are presented to set forth more clearly thesubject matter of this disclosure without imposing any limits on thescope thereof and to illustrate the clinical benefits of trigeminalnerve stimulation for the treatment of neuropsychiatric disorders. Inthe first example, patients with major depressive disorder were treatedby TNS with external transcutaneous electrodes. In the second example, apatient was treated using transcutaneous electrodes for bilateralsupraorbital stimulation.

EXAMPLE 1

FIGS. 5A-5C illustrate the results from a pilot study of externaltrigeminal nerve stimulation for the treatment of depression. Subjectswith major depression who met inclusion and exclusion criteria werefollowed for 8-weeks in an open label (unblinded) study conducted atUCLA.

Inclusion Criteria were: Age 18-65 years old who met DSM-IV criteria foran acute, recurrent episode of Major Depressive Disorder (MDD) and werein a major depressive episode (MDE) of moderate severity. Otherinclusion criteria were: the current MDE must be ≧4 months in duration,no response to at least one antidepressant over at least six weeksduring the current MDE, and concomitant use of at least oneantidepressant. All had prominent residual symptoms, with mean HamiltonDepression Rating Scale (HDRS-28) scores at study entry of 25.4 (3.9s.d.), range 19 to 29. Subjects placed stimulating electrodes over thesupraorbital branches of the trigeminal nerve for at least 8 hours perday (primarily while asleep), with current adjusted to maintaincomfortable levels. Five subjects completed the trial. Primary outcomewas change in HDRS at 8 weeks.

Exclusion criteria were: current pregnancy; meeting DSM-IV criteria foratypical or psychotic or bipolar depression; a history of schizophrenia,schizoaffective disorder, or other non-mood disorder psychosis; acurrent secondary DSM-IV diagnosis (or signs) of delirium, dementia,amnestic disorder or other cognitive disorder; clinically significantcurrent suicidal intent; significant cardiac, medical or progressiveneurological or medical illness; facial pain or trigeminal neuralgia; aVNS or other implantable electrical device such as a pacemaker; currentuse of a TENS or VNS unit, or history of non-compliance.

All subjects received unblinded TNS augmentation (adjunctive) treatmentfor at least 8-hours each day. Assessments were made at study intake,and at weeks 2, 4, 6, and 8 in the acute treatment phase. Subjects whowished to continue the treatment were allowed to participate in anoptional 6-month long-term extension phase with monthly monitoringvisits.

Subjects underwent stimulation using an electrical stimulator, such asfor example the EMS Model 7500 commercially available from TENSProducts, Inc. (www.tensproducts.com) operated at a frequency of 120Hertz, a current less than 20 mA, a pulse duration of 250 μsec, and aduty cycle at 30 seconds on and 30 seconds off, for a minimum of 8 hoursper day.

Prior to initiating treatment and at subsequent follow-up assessmentvisits, the symptom severity of each subject was quantified using theHamilton Depression Rating Scale (HDRS, scored using both 17- and28-item versions), the Beck Depression Inventory (BDI), and the QuickInventory of Depressive Symptomatology (QIDS), with the group averagevalues on each of these scales being tabulated in the table shown inFIG. 5A. All three are assessment instruments designed to measure theseverity of depression. The HDRS is a well-established rating scaleinstrument which is filled out by a clinician after interviewing andobserving the individual subject in order to measure the severity ofdepression; in this study, ratings on all 28 items (questions) weremade, and the scale was scored according to standard methods using allitems (HDRS₂₈) and the standard subset of 17 items (HDRS₁₇). The BDI isa 21-question multiple choice self-report survey that is used to measurethe severity of depression. The QIDS-C₁₆ is a 16-questionclinician-rated survey that is used to measure the severity ofdepression. Each of these scales affords different strengths andlimitations in assessing a patient's symptom severity (e.g. BDIemphasizes cognitive symptoms of depression, while the HDRS weightsneurovegetative symptoms prominently), and all are commonly used inclinical trials in major depression; the use of multiple scales alloweda more comprehensive assessment of the effects of trigeminal nervestimulation than any single scale in this initial study of thistreatment for major depression.

As shown in FIG. 5A, and graphically illustrated in FIGS. 5B and 5C,decreases in HDRS₂₈ were significant, from 25.4 (3.9 s.d.) at entry to13.6 (6.3 s.d.) at week 8 (2-tail t-test p<0.01, Cohen's d 2.4).Responses on the BDI similarly declined, from 26.8 (8.1) to 10.6 (4.9)(p<0.01, d 2.3). Decreases on the 16-item clinician-rated QIDS were alsosignificant, decreasing from 10.8 (3.4) to 5.5 (4.4) (p<0.05, d 1.3).Thus, significant decreases in symptom severity were achieved in the 8weeks of acute TNS treatment. Furthermore, changes in symptoms occurredacross all symptom areas, such as depressed mood, anxiety, sleep, andenergy. These findings support the use of TNS treatment which may alsohave use as an adjunct to pharmacotherapy when medications have failedto produce remission of symptoms.

EXAMPLE 2

FIG. 6 summarizes current, charge, current density and charge densityrecorded in a subject during exposure to transcutaneous stimulation ofthe supraorbital nerve. FIG. 6 illustrates representative parameters forbilateral supraorbital stimulation recorded in a subject using an EMS7500 stimulator, 120 HZ, 150-250 μsec, Tyco superior silver electrodes1.25″, one inch from the midline above the eyebrows. Data recorded withFluke Oscilloscope, 50 mV/div, resistor=10.1Ω. In general, these findingshow that as the pulse width increased, the maximum tolerable currentdecreased.

Transcutaneous electrical stimulation of the supraorbital branch of thetrigeminal nerve with round 1.25-inch TENS patch electrodes results incurrent densities and charge density/phase that are well within thelimits of safety. In general, the maximum current comfortably toleratedby TNS patients studied previously is approximately 25 mA's, andpatients typically are stimulated at an amplitude setting well below 25mA's (6-10 mA's).

The 1.25-inch TENS electrodes are circular electrodes with a radius of1.59 cm. The surface area can be calculated as A=πr²=[π]*[1.59 cm]²=7.92cm². Using these electrodes, typical stimulation current ranges from6-10 mA at pulse durations of 150-250 μsec.

Current Density: In a typical subject, stimulation currents of 6-10 mAresult in current densities ranging from 0.76 to 1.3 mA/cm². McCreery etal have established a maximum safe current density of 25 mA/cm at thestimulating electrode for transcranial electrical stimulation. Assumingeven higher currents of up to 25 mA with electrodes of surface area 7.92cm², current densities may range to a maximum of 3.16 mA/cm². From 0.76mA/cm² to 3.16 mA/cm², TNS delivers a current density 8-33 times lessthan the maximum safe allowable current density. Charge Density (Chargedensity/phase): Yuen et al have identified a safe limit for chargedensity/phase delivered at the cerebral cortex of 40 μC/cm². [Yuen et al1981] Assuming 10 mA at 250 μsec, the charge density/phase is [0.010A]×[250 μsec]/7.92=0.32 μC/cm² at the stimulating electrode. Assumingeven higher levels of stimulation, 25 mA at 250 μsec, the maximum chargedensity per phase is 0.79 μC/cm². At these levels, the charge density isgenerally 50 to 260 fold less at the stimulating electrode than themaximum allowed at the cerebral cortex. Since the cortex is a minimum of10-13 mm from the stimulating electrodes, and given the layers of skin,fat, bone, dura, and CSF, the actual charge densities will besignificantly lower.

As shown in FIG. 6, stimulation intensity responses in a subject withelectrodes of surface area 7.92 cm², at pulse durations between 150-250μsec, results in current densities at the scalp well below currentlyrecommended current densities for transcranial stimulation, which are 25mA/cm², and charge densities at the scalp significantly lower than safecharge densities at the cerebral cortex (0.15-0.18 μC/cm²).

From the foregoing discussion, it will be appreciated that the inventioncan be embodied in various ways which include, but which are not limitedto, the following:

1. A method of treating a neuropsychiatric disorder in a patient havinga trigeminal nerve, the method comprising: implanting at least oneelectrode in the patient in proximity to at least one superficial branchof the trigeminal nerve; and applying adjustable electric signals to atleast one superficial branch of the trigeminal nerve through the atleast one electrode.

2. The method of embodiment 1, wherein the at least one superficialbranch of the trigeminal nerve is a supraorbital nerve.

3. The method of embodiment 1, wherein the at least one superficialbranch of the trigeminal nerve is a infraorbital nerve.

4. The method of embodiment 1, wherein the at least one superficialbranch of the trigeminal nerve is a mentalis nerve.

5. The method of embodiment claim 1, wherein the step of applyingadjustable electric signals comprises applying electrical signals at afrequency of about 20 to 300 Hertz, at a constant current of 0.05 to 20milliamperes (mA), and a pulse duration of less than or equal to 500microseconds.

6. The method of embodiment 1, wherein the step of applying adjustableelectrical signals comprises applying electrical signals for less than12 hours per day.

7. An implantable device for stimulation of a superficial branch of atrigeminal nerve, the device comprising: at least two electrodes, eachelectrode having an upper contact point and a lower contact point, andeach electrode configured to be placed adjacent to a superficial branchof a trigeminal nerve; and means for connecting the at least twoelectrodes to an implanted neurostimulator; wherein adjustableelectrical signals generated by the implanted neurostimulator aretransmitted to a superficial branch of the trigeminal nerve via the atleast two electrodes.

8. A method of treating a neuropsychiatric disorder in a patient, themethod comprising: providing a device provided in accordance withembodiment 7; implanting the device in the patient such that the atleast two electrodes are placed adjacent to a superficial branch of thetrigeminal nerve; and applying an electric current to the device ofbetween 0.05 and 20 milliamperes, with a frequency of between 20 and 300Hertz with a pulse duration not exceeding 500 microseconds.

1. A subcutaneous electrode assembly for trigeminal nerve stimulation,the subcutaneous electrode assembly comprising: a first electrodecomprising a first pair of contacts configured for subcutaneousplacement at a first region of a patient's face; and a second electrodecomprising a second pair of contacts configured for subcutaneousplacement at a second region of a patient's face; wherein the first pairof contacts and the second pair of contacts are configured to bebilaterally implanted in proximity to, adjacent to or in contact with atleast one branch of the trigeminal nerve for treatment of aneuropsychiatric disorder by trigeminal nerve stimulation.

2. The subcutaneous electrode assembly of claim 1, wherein the at leastone branch of the trigeminal nerve is selected from the group consistingof: ophthalmic nerve, infraorbital nerve, mentalis nerve, supratrochlearnerve, infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacialnerve, zygomaticoorbital nerve, and auriculotemporal nerve.

3. A subcutaneous electrode assembly for trigeminal nerve stimulation,the subcutaneous electrode assembly comprising: a first electrodecomprising a first plurality of contacts configured for subcutaneousplacement at a first region of a patient's face; and a second electrodecomprising a second plurality of contacts configured for subcutaneousplacement at a second region of a patient's face; wherein the firstplurality of contacts and the second plurality of contacts areconfigured to be unilaterally implanted in proximity to, adjacent to orin contact with at least two different branches of the trigeminal nervefor treatment of a neuropsychiatric disorder by trigeminal nervestimulation.

4. The subcutaneous electrode assembly of claim 3, wherein the at leasttwo different branches of the trigeminal nerve are selected from thegroup consisting of: ophthalmic nerve, infraorbital nerve, mentalisnerve, supratrochlear nerve, infratrochlear nerve, zygomaticotemporalnerve, zygomaticofacial nerve, zygomaticoorbital nerve, andauriculotemporal nerve.

5. A method for treating a neuropsychiatric disorder or condition bytrigeminal nerve stimulation, comprising: implanting an electrodeassembly in a patient, the subcutaneous electrode assembly comprising: afirst electrode comprising a first plurality of contacts configured forsubcutaneous placement at a first region of the patient's face; a secondelectrode comprising a second plurality of contacts configured forsubcutaneous placement at a second region of the patient's face, whereinthe first plurality of contacts and the second plurality of contacts areconfigured to be implanted in proximity to, adjacent to or in contactwith at least one branch of the trigeminal nerve; and applyingelectrical signals to the electrode assembly at specified operationalparameters to treat a neuropsychiatric disorder.

6. The method of claim 5, wherein the step of applying electricalsignals comprises applying electrical signals at a frequency betweenapproximately 20 and 300 Hertz, at a current of 0.05 to 5 milliamperes(mA) and at a pulse duration of less than or equal to 500 microseconds.

7. The method of claim 5, wherein the step of applying electricalsignals comprises applying electrical signals at a frequency betweenapproximately 20 and 300 Hertz, at a current of 0.05 to 2 milliamperes(mA) and at a pulse duration not exceeding 500 microseconds.

8. The method of claim 5, wherein the neuropsychiatric disorder isdepression.

9. A system for trigeminal nerve stimulation for treatment of aneuropsychiatric disorder, the system comprising: a pulse generator; anda subcutaneous electrode assembly comprising: a first electrodecomprising a first plurality of contacts configured for subcutaneousplacement at a first region of the patient's face; and a secondelectrode comprising a second plurality of contacts configured forsubcutaneous placement at a second region of the patient's face, whereinthe first plurality of contacts and the second plurality of contacts areconfigured to be implanted in proximity to, adjacent to or in contactwith at least one branch of the trigeminal nerve

10. The system of claim 9 further comprising a wire operably connectingthe pulse generator and the subcutaneous electrode assembly.

11. The system of claim 9, wherein the at least one branch of thetrigeminal nerve is selected from the group consisting of: ophthalmicnerve, infraorbital nerve, mentalis nerve, supratrochlear nerve,infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacial nerve,zygomaticoorbital nerve, and auriculotemporal nerve.

12. A kit for trigeminal nerve stimulation for treatment of aneuropsychiatric disorder, the kit comprising: the subcutaneouselectrode assembly according to claim 1; and instructions for implantingthe electrode assembly in a patient for treatment of a neuropsychiatricdisorder or condition.

13. The kit of claim 12, further comprising: a pulse generator; andinstructions for applying electrical signals to the electrode assemblyfor treatment of a neuropsychiatric disorder or condition.

14. A kit for trigeminal nerve stimulation for treatment of aneuropsychiatric disorder, the kit comprising: the subcutaneouselectrode assembly according to claim 3; and instructions for implantingthe electrode assembly in a patient for treatment of a neuropsychiatricdisorder.

15. The kit of claim 14, further comprising: a pulse generator; andinstructions for applying electrical signals to the electrode assemblyfor treatment of a neuropsychiatric disorder.

16. A subcutaneous electrode assembly for trigeminal nerve stimulation,the subcutaneous electrode assembly comprising: a first electrodecomprising a first single contact configured for subcutaneous placementat a first region of a patient's face; and a second electrode comprisinga second single contact configured for subcutaneous placement at asecond region of a patient's face; wherein the first contact and thesecond contact are configured to be implanted in proximity to, adjacentto or in contact with at least one branch of the trigeminal nerve fortreatment of a neuropsychiatric disorder by trigeminal nervestimulation.

17. The subcutaneous electrode assembly of claim 16, wherein the atleast one branch of the trigeminal nerve is selected from the groupconsisting of: ophthalmic nerve, infraorbital nerve, mentalis nerve,supratrochlear nerve, infratrochlear nerve, zygomaticotemporal nerve,zygomaticofacial nerve, zygomaticoorbital nerve, and auriculotemporalnerve.

Those skilled in the art will appreciate that various adaptations andmodifications of the above described preferred embodiments may beconfigured without departing from the scope and spirit of thisdisclosure. Stimulation of the target nerve may be accomplished byapplication of energy in many forms, such as magnetic or ultrasonic.Therefore, it is to be understood that the subject matter of thisdisclosure may be practiced other than as specifically described herein.

What is claimed is:
 1. A system for trigeminal nerve stimulation fortreatment of a neuropsychiatric disorder, the system comprising: asubcutaneous electrode including: a first electrode comprising at leasta first contact and a second contact, wherein the first contact and thesecond contact are spaced apart according to a spacing between apatient's supraorbital nerve at a first side of the patient's foreheadand an adjacent supratrochlear nerve on the first side of the patient'sforehead.
 2. The system of claim 1, further comprising a secondelectrode comprising at least one contact configured for subcutaneousplacement at a second side of the patient's forehead, wherein the secondelectrode is configured to be implanted in proximity to, adjacent to orin contact with at least one branch of the trigeminal nerve, wherein theat least one branch of the trigeminal nerve is selected from the groupconsisting of: ophthalmic nerve, infraorbital nerve, mentalis nerve,supratrochlear nerve, infratrochlear nerve, zygomaticotemporal nerve,zygomaticofacial nerve, zygomaticoorbital nerve, nasal nerve, andauriculotemporal nerve.
 3. The system of claim 2, wherein the firstelectrode and the second electrode are configured for implantation inproximity to, adjacent to or in contact with a different branch of thetrigeminal nerve.
 4. The system of claim 1, further comprising: a pulsegenerator; and a wire operably connecting the pulse generator and thesubcutaneous electrode assembly.
 5. The system of claim 4, furthercomprising a regulating device configured to regulate a maximum chargebalanced output current below approximately 30-50 mA.
 6. The system ofclaim 1, wherein the neuropsychiatric disorder is selected from thegroup consisting of: mood disorder, cognitive disorder, behavioraldisorder and anxiety disorder.
 7. The system of claim 4, wherein thepulse generator is configured to apply electrical signals at a frequencybetween approximately 20 and 300 Hertz, at a pulse duration betweenapproximately 50 and 500 microseconds, at an output current density ofnot greater than approximately 25 mA/cm² and an output charge density ofnot greater than approximately 10 microCoulomb/cm² at the cerebralcortex.
 8. A subcutaneous electrode assembly for trigeminal nervestimulation for treatment of a neuropsychiatric disorder, the assemblycomprising: a first electrode comprising at least one contact configuredfor subcutaneous placement at a first region of the patient's face,wherein the first electrode is configured to be implanted in proximityto, adjacent to or in contact with at least one branch of the trigeminalnerve for treatment of a neuropsychiatric disorder by trigeminal nervestimulation, wherein the assembly is configured for minimal currentpenetration into a brain of a patient, and wherein the at least onebranch of the trigeminal nerve is selected from the group consisting of:ophthalmic nerve, infraorbital nerve, mentalis nerve, supratrochlearnerve, infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacialnerve, zygomaticoorbital nerve, nasal nerve, and auriculotemporal nerve.9. The assembly of claim 8, further comprising a second electrodecomprising at least one contact configured for subcutaneous placement ata second region of the patient's face, wherein the second electrode isconfigured to be implanted in proximity to, adjacent to or in contactwith at least one branch of the trigeminal nerve, wherein the at leastone branch of the trigeminal nerve is selected from the group consistingof: ophthalmic nerve, infraorbital nerve, mentalis nerve, supratrochlearnerve, infratrochlear nerve, zygomaticotemporal nerve, zygomaticofacialnerve, zygomaticoorbital nerve, nasal nerve, and auriculotemporal nerve.10. The assembly of claim 9, wherein the first electrode and the secondelectrode are configured for implantation in proximity to, adjacent toor in contact with a same branch of the trigeminal nerve.
 11. Theassembly of claim 9, wherein the first electrode and the secondelectrode are configured for implantation in proximity to, adjacent toor in contact with a different branch of the trigeminal nerve.
 12. Theassembly of claim 9, wherein the neuropsychiatric disorder is selectedfrom the group consisting of: mood disorder, cognitive disorder,behavioral disorder and anxiety disorder.